Conformational Control of [2]Rotaxane by Hydrogen Bond

A series of [2]rotaxanes with various functional groups in the axle component was synthesized by the oxidative dimerization of alkynes, which is mediated by a macrocyclic phenanthroline–Cu complex. The rotaxanes were fully characterized by spectroscopic methods, and the structure of a rotaxane was determined by X-ray crystallographic analysis. The interaction between the ring component and the axle component was studied in detail to understand the conformation of the rotaxanes. The presence of the hydrogen bond between the phenanthroline moiety in the macrocyclic component and the acidic proton in the axle component influenced the conformation of rotaxane.


■ INTRODUCTION
[2]Rotaxane is an important class of interlocked compounds, and extensive studies related to the synthesis, structure, and dynamic behavior have been reported. 1 Following the seminal study of Dietrich−Buchecker and Sauvage, who reported the synthesis of [2]catenates from macrocyclic phenanthrolines by the metal-template method, 2 Gibson and co-workers reported the synthesis of [2]rotaxane based on a similar strategy. 3 These synthetic approaches were extensively applied to the synthesis of various interlocked compounds. 4 Recent development of the synthetic methods related to interlocked compounds includes the use of a macrocyclic metal complex as a promotor for the bond-forming reaction. The metal-mediated reaction proceeded inside the macrocyclic metal complex so that the interlocked compounds could be synthesized efficiently. 5 Leigh and co-workers reported the first example of this approach, who employed a macrocyclic pyridine−Cu complex. 6 Assuming that the Cu complex could mediate coupling reactions such as the oxidative dimerization of alkynes (Glaser coupling), we reported the synthesis of [2]rotaxanes from macrocyclic phenanthroline−Cu complex and alkynes with bulky substituents (Scheme 1). 7 Interlocked compounds with polyyne structures have been synthesized by this method, and the properties of these compounds have been studied by several research groups. 8 We have been interested in the conformation of [2]rotaxane with a macrocyclic phenanthroline ring. The phenanthroline moiety of the ring component would interact with the acidic hydrogen atom located in the axle component and the conformation of the [2]rotaxane could be affected, especially when the size of the ring component is small. 9 In this paper, we report the synthesis of small [2]rotaxanes with functionalized axle components (Scheme 2). The interaction between the ring and axle components was studied to understand the conformation of [2]rotaxanes.
The syntheses of the alkynes 3a−i are summarized in Schemes 4 and 5.
Tris([1,1′-biphenyl]-4-yl)methanol reacted with aniline hydrochloride under acidic conditions, and the substituted aniline 5 10 was isolated in 64% yield (Scheme 4). Aniline 5 was converted to aryl iodide 6 by the Sandmeyer reaction. 11 Compound 6 was further converted to alkynes with various functional groups. For example, the Sonogashira reaction of 6 with (trimethylsilyl)acetylene and the removal of the trimethylsilyl (TMS) group gave 3a in 83% yield. Similarly, the reaction of 6 with 7 12 gave alkyne 3b in comparable yield. Iodide 6 was converted to boronic acid 8 in 66% yield. The introduction of the benzyl group was achieved by the Suzuki− Miyaura reaction of 8 with 4-(trimethylsilylethynyl)benzyl bromide 9. 13 The deprotection of 10 under basic conditions gave 3c in 85% yield. An N-methylaniline derivative 11 was synthesized by the reaction of tris([1,1′-biphenyl]-4-yl)methanol and N-methylaniline hydrochloride in 21% yield. Compound 11 reacted with iodide 12 14 to give 13 in 76% yield, 15 and further removal of the TMS group gave 3d in 63% yield.
Secondary amine 3f was prepared by the Pd-catalyzed arylation of 5 and the removal of the TMS group (Scheme 5). Amide 3h was synthesized by the condensation of 5 with acid Scheme 1. Synthesis of [2]Rotaxane by Glaser Coupling 7a Scheme 2. Synthesis of Small [2]Rotaxanes with a Functionalized Axle Component The Journal of Organic Chemistry pubs.acs.org/joc Article 15. 16 The reduction of 3h gave amine 3g in a high yield. Fluorenylmethoxycarbonyl (Fmoc)-protected compound 3e was synthesized by treating 3g with FmocCl. Triazole derivative 3i was prepared from 6 in three steps. 6 Synthesis of [2]Rotaxanes. With the axle precursors in hand, we studied the synthesis of rotaxanes by the reaction of 2 with 3a−i. The results are summarized in Table 1.
A mixture of phenanthroline−Cu complex 2 (1 equiv), alkyne 3a (2.5 equiv), I 2 (1.0 equiv), and K 2 CO 3 (10 equiv) in tetrahydrofuran (THF) was heated at 60°C for 24 h. To the mixture was added I 2 (1.0 equiv) and K 2 CO 3 (10 equiv), and the resulting mixture was heated again for 24 h. After the removal of the Cu ion by ammonia, product 4a was isolated in 86% yield (entry 1, procedure A). Alkynes 3b and 3c were reacted with 2 under the same conditions, and [2]rotaxanes were isolated in 49% (4b) and 39% (4c) yields, respectively (entries 2 and 3). The yield of rotaxane decreased when 3d was employed as the starting material (28%, entry 4). Rotaxane 4e was isolated in 47% yield under modified conditions using smaller amounts of K 2 CO 3 (3.75 equiv) and I 2 (1.25 equiv, entry 5, procedure B): to prevent the cleavage of the Fmoc group, KCN was used to remove the Cu ion. The synthesis of 4f was examined under two reaction conditions, and the yield was better (60%) when procedure B was employed (entries 6 and 7). The reaction of benzylamine derivative 3g gave the corresponding rotaxane 4g in very low yield regardless of the procedures (entries 8 and 9). We assumed that the diarylamino group induced the removal of the copper ion from the phenanthroline moiety and suppressed the formation of rotaxane. Compound 4g was synthesized in a better yield by the removal of the Fmoc group from 4e (Scheme 6). Rotaxanes 4h and 4i were synthesized in 46% and 48% yields, respectively, by procedure A (entries 10 and 11).
The structure of 4a was elucidated by X-ray crystallographic analysis, and the results are summarized in Figure 1. The molecular structure of 4a provided insights into the conformation of the rotaxanes. In the molecular structure obtained by the recrystallization of 4a from hexane−toluene, short contacts between the C sp carbon atoms and the hydrogen atoms bound to the aromatic ring were observed (Figure 1a). 8f We also succeeded in determining the molecular structure of 4a from another sample, which was obtained by the recrystallization of 4a from methyl tert-butyl ether (MTBE)− chloroform ( Figure 1b). In the structure, the C−H···N interaction between chloroform and the phenanthroline moiety, in addition to the short contact between the C sp carbon atom and the hydrogen atom, was detected ( Figure  1b). A similar interaction has been reported in the literature. 17 Comparison of the 1 H NMR Spectra of [2]Rotaxanes. Further analysis of the structure and conformation of [2]rotaxanes was done by 1 H NMR spectroscopy. In the spectra of [2]rotaxanes we studied, sharp signals were detected in most compounds and the localization of the ring component to a specific position was not observed at rt. 18,19 Based on these results, we assume that the movement of the ring component along the axle component is fast, and the observed chemical shifts are the average of the conformers. Partial 1 H NMR spectra of ring component 1 and [2]rotaxanes (4a−i) are shown in Figure 2. We assigned the signals 20 that correspond to H d , H e , and H f of the macrocyclic components, and the chemical shifts were compared (Table 2). Based on the observed chemical shifts, rotaxanes were classified into two groups. In the compounds classified into group A (4a−e), the chemical shifts of H d , H e , and H f appeared at 8.3−8.5, 7.1−7.2, and 7.0−7.1 ppm, respectively. It is noteworthy that the difference in the chemical shifts is small, regardless of the structure of the axle moiety. The chemical shifts of H d and H e in the phenanthroline moiety are similar to those of macrocyclic phenanthroline 1, while the chemical shift of H f , which is bound to the resorcinol framework, shifted downfield (0.4−0.5 ppm) compared to the corresponding signal of 1. Because a larger difference of the chemical shift in the resorcinol moiety was induced by the formation of the [2]rotaxane, we assume that the "distance" 21 between the resorcinol moiety and the axle component is short: the axle Scheme 5. Synthesis of Precursors 3e−i   The Journal of Organic Chemistry pubs.acs.org/joc Article Furthermore, the difference in the chemical shifts strongly depends on the structure of the axle moiety, implying that the axle moiety is located in the proximity of the phenanthroline moiety. Next, we compared the chemical shifts of rotaxanes (4) with those of the corresponding axle components (17, Table 3). The difference between the chemical shifts of the methylene group (H y ) of 4c and 17c was small (ΔH y = −0.19 ppm): in rotaxane 4c, the signal appeared at 3.77 ppm, while the corresponding signal appeared at 3.96 ppm in 17c. A similar trend was observed when we compared the chemical shift of the methyl group of 4d with that of 17d. The difference between the chemical shifts of the methyl group was small (ΔH y = −0.16 ppm). Rotaxanes 4c and 4d belong to group A. When similar analyses were conducted with rotaxanes that belongs to group B, the difference in the chemical shifts was significantly large. The chemical shift (7.68 ppm) of the proton bound to the nitrogen atom in rotaxane (4f), for example, shifted upfield (5.87 ppm) in the axle component (17f): the difference in the chemical shifts was large (ΔH y = 1.81 ppm).
Similar results were obtained when we compared the chemical shifts of rotaxanes 4g−i with diynes 17g−i. The signal assigned to H y in 4g−i shifted upfield (1.03−1.67 ppm) in 17g−i.
The results summarized in Tables 2 and 3 could be explained by assuming the presence (or absence) of the hydrogen bond between the axle component and the ring component of rotaxane. In 4c, which belong to group A, no strong interaction between the axle component and the ring component would be present, and the axle component would be located in the proximity of the resorcinol moiety to minimize the steric interaction between the bulky phenanthroline moiety and the axle component ( Figure 3). Consequently, the chemical shifts of H d , H e , and H y are less affected by the presence of the axle component, while the signal of H f shift downfield. The situation would change significantly in the rotaxanes that belong to group B.
In 4f, for example, the presence of the hydrogen bond between the axle component and the ring component would affect the conformation of rotaxane ( Figure 3). The axle  The formation of the hydrogen bond between the acidic triazole proton and the amine moiety in [2]rotaxane has been postulated by several research groups. 22,23 If the conformation of rotaxane was influenced by the presence of the hydrogen bond, a notable solvent effect on the chemical shifts of rotaxanes would be observed. In a highly polar solvent, the hydrogen bond between the axle component and the ring component would be cleaved, and this would affect the conformation as well as the chemical shifts of rotaxanes. To confirm the presence of the intramolecular hydrogen bond, we selected 4c, in which the intramolecular hydrogen bond would not be present, and 4f, in which the hydrogen bond between the phenanthroline moiety and the amino group would be present. We observed the 1 H NMR    Table 4. When we observed the 1 H NMR spectra of 4c and 4f in DMSO-d 6 , the difference in the chemical shifts of H d , H e , and H f was small (less than 0.2 ppm), implying that 4c and 4f would adopt a similar conformation in DMSO-d 6 (Table 4). Meanwhile, the 1 H NMR spectra of 4c and 4f were different in CDCl 3 . In the NMR spectrum of 4c, the signal of H f shifted downfield (0.44 ppm) compared to the corresponding signal of macrocyclic phenanthroline 1, and the difference in other signals (H d and H e ) was negligible. 24 The result implies that the axle component of 4c is located in the proximity of the resorcinol moiety ( Figure 3). In contrast, the chemical shifts of H d and H e shifted upfield (0.76 and 0.50 ppm, respectively) in 4f compared to the corresponding signals of 1, while the difference in the chemical shifts of H f was small (0.04 ppm). The result could be explained by postulating the presence of the intramolecular hydrogen bond between the axle component and the ring component of 4f ( Figure 3). The axle component of 4f would be located in the proximity of the phenanthroline moiety, and the chemical shifts of H d and H e would be strongly affected.
The presence of the intramolecular hydrogen bond was also supported by comparing the 1 H NMR chemical shifts of the axle moiety of rotaxanes and related compounds in different solvents ( Table 5). The difference in the chemical shifts of the methylene group of 4c and that of 17c in DMSO-d 6 was small (−0.20 ppm). Similar results were observed when the chemical shifts of the NH group of 4f and that of 17f in DMSO-d 6 were compared or the chemical shifts of the methylene group of 4c and that of 17c in CDCl 3 were compared. In contrast, a large difference (1.81 ppm) was observed when the chemical shifts of the NH group of 4f and that of 17f in CDCl 3 were compared. The results could be reasonably interpreted by postulating that the intramolecular hydrogen bond is present in a solution of 4f in CDCl 3 . 25 Variable-Temperature 1 H NMR Experiments. We assumed that the conformation of [2]rotaxanes of group B adopted a structure with a low symmetry ( Figure 3b). The observed NMR spectra at 295 K, however, do not directly correspond to the assumed conformation; the signals of the two dumbbell moieties, for example, were equivalent. The observed NMR spectra of [2]rotaxanes of group B could be explained in terms of the fast shuttling of the ring component at 295 K ( Figure 5). 22,26 Expecting that the rate of the shuttling would decrease at low temperatures and that the signals that reflect the less symmetric structure of [2]rotaxane would appear, we conducted the variable-temperature 1 H NMR experiments of 4c, 4f, and 4h in CD 2 Cl 2 . When the 1 H NMR spectrum of 4c, a negative control, was observed at low temperatures, only the broadening of the signals was observed, and the difference in the chemical shifts was small ( Figure S1). Similar results were obtained when the 1 H NMR spectrum of 4f, a rotaxane that would form a hydrogen bond, was recorded ( Figure S2). In 4h, on the other hand, the chemical shift of the amide group (H y , 11.59 ppm) at 188 K was downfield (1.6 ppm) compared to the corresponding signal at 203 K (9.95 ppm, Figure 6). We assume that the signal observed at 203 K (9.95 ppm) split into two signals at a low temperature (188 K). One signal that appeared at 11.59 ppm would correspond to the amide proton that interacted with the phenanthroline moiety by the hydrogen bond, and the other signal was not detected because the signal overlapped with other signals. 27 Based on the observed data, the activation energy for the shuttling process of 4h was assumed to be 8 kcal/mol. 28    We anticipated that the N−H···N interaction would be stronger in a less polar solvent and observed the 1 H NMR spectra of 4f in toluene-d 8 (Figure 7c, bottom). Notably, two NH signals were observed at 4.86 and 10.70 ppm at 193 K. We confirmed that these signals correspond to the amino group by observing the 1 H NMR spectra of the deuterated compound 4f-d 2 (78 atom % D of the N−D bond, Figure 7b, middle). Because the signal of the amino group of 17f (the axle component of 4f) was observed at 4.83 ppm in toluene-d 8 at 193 K (Figure 7a, top), the signal of 4f, which appeared at 4.86 ppm, could be assigned to the free amino group, while the signal observed at 10.70 ppm would correspond to the amino group that interacted with the phenanthroline moiety. The amino groups in 4f appeared as two non-equivalent signals at 193 K due to the decrease in the rate of the shuttling. 8h,30

■ CONCLUSIONS
In summary, we synthesized [2]rotaxanes with various functional groups and studied the conformation of the compounds. The comparison of 1 H NMR spectra of [2]rotaxanes and related components in CDCl 3 showed that the spectra of rotaxanes were significantly affected by the structure of the axle component. The result could be explained by postulating the presence of the intramolecular hydrogen bond between the phenanthroline moiety and the acidic hydrogen atom in the axle component. The observation of some non-equivalent 1 H NMR signals at low temperatures supports the idea that the shuttling of the ring component occurs in some rotaxanes that form hydrogen bonds. The study would contribute to the understanding of the conformation of the interlocked compounds.
■ EXPERIMENTAL SECTION General Methods. Reagents were commercially available and were used without further purification. An oil bath or a bead bath was used as the heat source, and the external temperature was reported. NMR spectra were recorded on a JEOL 400 or 500 MHz spectrometer or a Bruker 400 MHz NMR spectrometer. Chemical shifts were reported in delta units (δ) relative to chloroform (7.24 ppm for 1 H NMR and 77.0 ppm for 13 C NMR) or dimethyl sulfoxide (DMSO) (2.50 ppm for 1 H NMR and 39.5 ppm for 13 C NMR). Multiplicity is indicated by s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), or br (broad). Coupling constants, J, are reported in Hertz. IR spectra were recorded on a Fourier transform infrared spectrometer using a diamond ATR module. A YMC-GPC T30000 (21.2 mm ID × 600 mm L) column was used for GPC separation using CHCl 3 as the eluent. Thin layer chromatography was performed on Merck silica gel 60F-254 plates. Column chromatography was performed using Kanto Chemical silica gel 60N (spherical, neutral 40−50 μm). High-resolution mass spectra (HRMS) were obtained by using a time-of-flight (TOF) mass analyzer.
Preparation and Observation of the 1 H NMR Spectrum of 4f-d 2 . A solution of 4f (27 mg, 0.014 mmol) in CH 3 OD (99 atom % D, 1.2 mL) and anhydrous dichloromethane (1.2 mL) was stirred at rt under Ar overnight. Volatiles were removed under reduced pressure to yield the desired deuterated compound, 4f-d 2 (26 mg, 0.014 mmol, quint, 78 atom % D of the N−D bond, estimated by 1 H NMR in CDCl 3 ) as a light yellow solid.
In order to reduce the deuteration loss due to water and possible residual acidic impurities in the solvent used for recording NMR, it was imperative to include a simple pre-treatment for these solvents. NMR solvents (CDCl 3 for confirming deuteration and deuterated toluene-d 8 for VT NMR experiments) were thoroughly washed with equal volume of D 2 O followed by drying over sodium sulfate before use.
X-ray Diffraction Studies. A suitable single crystal was selected in Fomblin Y perfluoropolyether (HVAC 140/13) at ambient temperature. All diffraction data were collected at −173°C on a Bruker Apex II Ultra X-ray diffractometer equipped with a Mo Kα radiation (λ = 0.71073 Å) source. Intensity data were processed using the Apex3 software suite. The solution of the structures and the corresponding refinements were carried out using the Yadokari-XG 31 graphical interface. The positions of the non-hydrogen atoms were determined by using the SHELXT-2014/5 and 2018/2 32 program and refined on F 2 by the full-matrix least-squares technique using the SHELXL-2018/3 33 program. All non-hydrogen atoms were refined with anisotropic thermal parameters, while all hydrogen atoms were placed using AFIX instructions.
Compound 4a(b): C 128 H 96 N 2 O 4 ·CHCl 3 ·(solvents). Single crystals for X-ray diffraction were grown from CHCl 3 /MTBE solution. Accessible voids were found in the unit cell. Attempts to model the solvent molecules (CHCl 3 , MTBE, and/or H 2 O) were not successful due to heavy disorder of the molecules. The diffuse electron density associated with the solvent molecules was removed by the PLATON/ SQUEEZE 34 program. The diffraction data are summarized in Table  S2.
VT-NMR studies, copies of 1 H and 13 C NMR spectra of new compounds, 2D NMR spectra, the diffraction data, HRMS data of [2]rotaxanes, and X-ray data for 4a(a) and 4a(b) (PDF)